Ano-genital human papillomaviruses contribute significantly to sexually transmitted disease in the United States and worldwide. A subset of these viruses, the "high risk" HPVs, is recognized to be the etiological agent for cervical cancer, the second leading cause of death by cancer among women worldwide. An effective mechanism for inhibiting the transmission of ano-genital HPVs, therefore, would be of significant value to improving the health of women. In preliminary studies in collaboration with Dr. Curtis Brandt, the PL has discovered that a peptide (EB), previously shown by Dr. Brandt to inhibit HSV-1 infection, can inhibit the infection-mediated transforming activity of bovine papillomavirus type 1 (BPV-1 ), a prototype papi1lomavirus. These preliminary studies provide a basis for the Project described here. The applicant proposes to study the mechanism of action by which these or like drugs act to inhibit BPV-1 transformation, determine if the drug(s) inhibits ano-genital HPVs, screen alternative peptides to identify more effective drugs, and establish an in vivo infection assay for ano-genital HPVs with which to assess better the clinical applicability of these antiviral drugs in preventing transmission of papillomaviruses. A critical component of this Project is the generation of a "preclinical" animal model system for assessing HPV infectivity. This model system will permit the applicant to assess the effectiveness of drugs in inhibiting the infectivity of ano-genital HPVs in vivo. This preclinical model makes use of recent advances made in the applicant?s laboratory in recapitulating the human papillomavirus life cycle in human epithelial cells in tissue culture that can be used as a source of human epithelial cell xenografts on nude mice.